title: Ezrin regulates the expression of Mrp2/Abcc2 and Mdr1/Abcb1 along the rat small intestinal tract.
abstract: Multidrug resistance-associated protein 2 (MRP2)/ATP-binding cassette protein C2 (ABCC2) and multidrug resistance protein 1 (MDR1)/ABCB1 are well-known efflux transporters located on the brush border membrane of the small intestinal epithelia, where they limit the absorption of a broad range of substrates. The expression patterns of MRP2/ABCC2 and MDR1/ABCB1 along the small intestinal tract are tightly regulated. Several reports have demonstrated the participation of ERM (ezrin/radixin/moesin) proteins in the posttranslational modulation of MRP2/ABCC2 and MDR1/ABCB1, especially with regard to their membrane localization. The present study focused on the in vivo expression profiles of MRP2/ABCC2, MDR1/ABCB1, ezrin, and phosphorylated ezrin to further elucidate the relationship between the efflux transporters and the ERM proteins. The current results showed good correlation between the phosphorylation status of ezrin and Mrp2/Abcc2 expression along the gastrointestinal tract of rats and between the expression profiles of both ezrin and Mdr1/Abcb1 in the small intestine. We also demonstrated the involvement of conventional protein kinase C isoforms in the regulation of ezrin phosphorylation. Furthermore, experiments conducted with wild-type (WT) ezrin and a T567A (Ala substituted Thr) dephosphorylated mutant showed a decrease in membrane surface-localized and total expressed MRP2/ABCC2 in T567A-expressing vs. WT ezrin-expressing Caco-2 cells. In contrast, T567A- and WT-expressing cells both showed an increase in membrane surface-localized and total expressed MDR1/ABCB1. These findings suggest that the phosphorylation status and the expression profile of ezrin differentially direct MRP2/ABCC2 and MDR1/ABCB1 expression, respectively, along the small intestinal tract.
authors.affiliation: Faculty of Pharmaceutical Sciences, Teikyo Heisei University, 4-21-2 Nakano, Nakano-ku, Tokyo 164-8530, Japan. t.horie@thu.ac.jp.
authors.forename: Takafumi
authors.initials: T
authors.lastname: Nakano
authors.forename: Shuichi
authors.initials: S
authors.lastname: Sekine
authors.forename: Kousei
authors.initials: K
authors.lastname: Ito
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Horie
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism*; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D018938:Caco-2 Cells; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism*; D007421:Intestine, Small / Q000166:cytology / Q000378:metabolism*; D000089762:Multidrug Resistance-Associated Protein 2; D020125:Mutation, Missense; D010766:Phosphorylation; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D051381:Rats; D017207:Rats, Sprague-Dawley; D000099149:Ezrin
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D018528:ATP-Binding Cassette Transporters; D003598:Cytoskeletal Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D011493:Protein Kinase C; D000099149:Ezrin; C000715087:ABCC2 protein, human; C423013:Abcc2 protein, rat; C095122:multidrug resistance protein 3
keywords: MDR1/ABCB1; MRP2/ABCC2; ezrin; small intestinal tract